Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Arifa, Raquel Duque Nascimento; Madeira, Mila Fernandes Moreira; Paula, Talles Prosperi de; Lima, Renata Lacerda; Tavares, Lívia D.; Menezes‐Garcia, Zélia; Fagundes, Caio T.; Rachid, Milene Alvarenga; Ryffel, Bernhard; Zamboni, Dario S.; Teixeira, Mauro Martins; Souza, Danielle G.

doi:10.1016/j.ajpath.2014.03.012

Cited by 60 publications

(55 citation statements)

References 52 publications

(35 reference statements)

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“…It was recently reported that mitochondrial ROS may promote inflammation by activating the multiprotein cytoplasmic complexes inflammasome NLRP3 [34,35]. NLRP3 inflammasome activation leads to caspase-1 activation and subsequent cleavage of pro-cytokines, such as IL-1β, into their mature forms.…”

Section: Resultsmentioning

confidence: 99%

Melatonin protects rats from radiotherapy-induced small intestine toxicity

et al. 2017

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Radiotherapy-induced gut toxicity is among the most prevalent dose-limiting toxicities following radiotherapy. Prevention of radiation enteropathy requires protection of the small intestine. However, despite the prevalence and burden of this pathology, there are currently no effective treatments for radiotherapy-induced gut toxicity, and this pathology remains unclear. The present study aimed to investigate the changes induced in the rat small intestine after external irradiation of the tongue, and to explore the potential radio-protective effects of melatonin gel. Male Wistar rats were subjected to irradiation of their tongues with an X-Ray YXLON Y.Tu 320-D03 irradiator, receiving a dose of 7.5 Gy/day for 5 days. For 21 days post-irradiation, rats were treated with 45 mg/day melatonin gel or vehicle, by local application into their mouths. Our results showed that mitochondrial oxidative stress, bioenergetic impairment, and subsequent NLRP3 inflammasome activation were involved in the development of radiotherapy-induced gut toxicity. Oral treatment with melatonin gel had a protective effect in the small intestine, which was associated with mitochondrial protection and, consequently, with a reduced inflammatory response, blunting the NF-κB/NLRP3 inflammasome signaling activation. Thus, rats treated with melatonin gel showed reduced intestinal apoptosis, relieving mucosal dysfunction and facilitating intestinal mucosa recovery. Our findings suggest that oral treatment with melatonin gel may be a potential preventive therapy for radiotherapy-induced gut toxicity in cancer patients.

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Section: Resultsmentioning

confidence: 99%

Melatonin protects rats from radiotherapy-induced small intestine toxicity

et al. 2017

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“…It was recently reported that ROS-activated inflammasome increases intestinal mucositis in mice treated with chemotherapeutic agent, irinotecan [37]. Administration of IL-1 receptor antagonist to the mouse model also reduces 5-FU-induced intestinal mucositis [38].…”

Section: Discussionmentioning

confidence: 96%

Preventive Effect of Daiokanzoto (TJ-84) on 5-Fluorouracil-Induced Human Gingival Cell Death through the Inhibition of Reactive Oxygen Species Production

et al. 2014

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Daiokanzoto (TJ-84) is a traditional Japanese herbal medicine (Kampo formulation). While many Kampo formulations have been reported to regulate inflammation and immune responses in oral mucosa, there is no evidence to show that TJ-84 has beneficial effects on oral mucositis, a disease resulting from increased cell death induced by chemotherapeutic agents such as 5-fluorouracil (5-FU). In order to develop effective new therapeutic strategies for treating oral mucositis, we investigated (i) the mechanisms by which 5-FU induces the death of human gingival cells and (ii) the effects of TJ-84 on biological events induced by 5-FU. 5-FU-induced lactate dehydrogenase (LDH) release and pore formation in gingival cells (Sa3 cell line) resulted in cell death. Incubating the cells with 5-FU increased the expression of nucleotide-binding domain and leucine-rich repeat containing PYD-3 (NLRP3) and caspase-1. The cleavage of caspase-1 was observed in 5-FU-treated cells, which was followed by an increased secretion of interleukin (IL)-1β. The inhibition of the NLRP3 pathway slightly decreased the effects of 5-FU on cell viability and LDH release, suggesting that NLRP3 may be in part involved in 5-FU-induced cell death. TJ-84 decreased 5-FU-induced LDH release and cell death and also significantly inhibited the depolarization of mitochondria and the up-regulation of 5-FU-induced reactive oxygen species (ROS) and nitric oxide (NO) production. The transcriptional factor, nuclear factor-κB (NF-κB) was not involved in the 5-FU-induced cell death in Sa3 cells. In conclusion, we provide evidence suggesting that the increase of ROS production in mitochondria, rather than NLRP3 activation, was considered to be associated with the cell death induced by 5-FU. The results also suggested that TJ-84 may attenuate 5-FU-induced cell death through the inhibition of mitochondrial ROS production.

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“…Production of reactive oxygen and nitrogen species and oxidative stress are wellcharacterized upstream mediators of NF-κB activation as well as inflammasomes [51,52]. Oxygen radical scavengers and antioxidant enzymes, such as superoxide dismutase, have shown promise as anti-mucotoxic agents [53][54][55]. As such, there remains a clear benefit to targeting NF-κB-mediated inflammatory signaling, including upstream and downstream regulators, for prevention of oral and intestinal mucositis.…”

Section: Sophisticated Targeting Of Inflammationmentioning

confidence: 99%

The pathogenesis of mucositis: updated perspectives and emerging targets

Bowen

Al‐Dasooqi²,

Bossi

et al. 2019

Support Care Cancer

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Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.

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Inflammasome Activation Is Reactive Oxygen Species Dependent and Mediates Irinotecan-Induced Mucositis through IL-1β and IL-18 in Mice

Cited by 60 publications

References 52 publications

Melatonin protects rats from radiotherapy-induced small intestine toxicity

Melatonin protects rats from radiotherapy-induced small intestine toxicity

Preventive Effect of Daiokanzoto (TJ-84) on 5-Fluorouracil-Induced Human Gingival Cell Death through the Inhibition of Reactive Oxygen Species Production

The pathogenesis of mucositis: updated perspectives and emerging targets

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